Mutation Patterns Research Articles

A fungal plant pathogen overcomes mlo-mediated broad-spectrum disease resistance by rapid gene loss.

Hosts and pathogens typically engage in a coevolutionary arms race. This also applies to phytopathogenic powdery mildew fungi, which can rapidly overcome plant resistance and perform host jumps. Using experimental evolution, we show that the powdery mildew pathogen Blumeria hordei is capable of breaking the agriculturally important broad-spectrum resistance conditioned by barley loss-of-function mlo mutants. Partial mlo virulence of evolved B. hordei isolates is correlated with a distinctive pattern of adaptive mutations, including small-sized (c. 8-40 kb) deletions, of which one is linked to the de novo insertion of a transposable element. Occurrence of the mutations is associated with a transcriptional induction of effector protein-encoding genes that is absent in mlo-avirulent isolates on mlo mutant plants. The detected mutational spectrum comprises the same loci in at least two independently isolated mlo-virulent isolates, indicating convergent multigenic evolution. The mutational events emerged in part early (within the first five asexual generations) during experimental evolution, likely generating a founder population in which incipient mlo virulence was later stabilized by additional events. This work highlights the rapid dynamic genome evolution of an obligate biotrophic plant pathogen with a transposon-enriched genome.

Graph-Based Pan-Genome Reveals the Pattern of Deleterious Mutations during the Domestication of Saccharomyces cerevisiae.

The "cost of domestication" hypothesis suggests that the domestication of wild species increases the number, frequency, and/or proportion of deleterious genetic variants, potentially reducing their fitness in the wild. While extensively studied in domesticated species, this phenomenon remains understudied in fungi. Here, we used Saccharomyces cerevisiae, the world's oldest domesticated fungus, as a model to investigate the genomic characteristics of deleterious variants arising from fungal domestication. Employing a graph-based pan-genome approach, we identified 1,297,761 single nucleotide polymorphisms (SNPs), 278,147 insertion/deletion events (indels; <30 bp), and 19,967 non-redundant structural variants (SVs; ≥30 bp) across 687 S. cerevisiae isolates. Comparing these variants with synonymous SNPs (sSNPs) as neutral controls, we found that the majority of the derived nonsynonymous SNPs (nSNPs), indels, and SVs were deleterious. Heterozygosity was positively correlated with the impact of deleterious SNPs, suggesting a role of genetic diversity in mitigating their effects. The domesticated isolates exhibited a higher additive burden of deleterious SNPs (dSNPs) than the wild isolates, but a lower burden of indels and SVs. Moreover, the domesticated S. cerevisiae showed reduced rates of adaptive evolution relative to the wild S. cerevisiae. In summary, deleterious variants tend to be heterozygous, which may mitigate their harmful effects, but they also constrain breeding potential. Addressing deleterious alleles and minimizing the genetic load are crucial considerations for future S. cerevisiae breeding efforts.

A Comparative Analysis of the Immunoglobulin Repertoire in Leukemia Cells and B Cells in Chinese Acute Myeloid Leukemia by High-Throughput Sequencing.

It is common knowledge that immunoglobulin (Ig) is produced by B lymphocytes and mainly functions as an antibody. However, it has been shown recently that myeloblasts from acute myeloid leukemia (AML) could also express Ig and that AML-Ig played a role in leukemogenesis and AML progression. The difference between Ig from myeloblasts and B cells has not been explored. Studying the characteristics of the Ig repertoire in myeloblasts and B cells will be helpful to understand the function and significance of AML-Ig. We performed 5' RACE-related PCR coupled with PacBio sequencing to analyze the Ig repertoire in myeloblasts and B cells from Chinese AML patients. Myeloblasts expressed all five classes of IgH, especially Igγ, with a high expression frequency. Compared with B-Ig in the same patient, AML-Ig showed different biased V(D)J usages and mutation patterns. In addition, the CDR3 length distribution of AML-Ig was significantly different from those of B-Ig. More importantly, mutations of AML-IgH, especially Igμ, Igα, and Igδ, were different from that of B-IgH in each AML patient, and the mutations frequently occurred at the sites of post-translational modification. AML-Ig has distinct characteristics of variable regions and mutations, which may have implications for disease monitoring and personalized therapy.

Cross-species substitution matrix comparison of Tomato leaf curl New Delhi virus (ToLCNDV) with medicinal plant isolates

The main objective of this study was to estimate and compare substitution matrixes of nucleotide frequencies for Tomato leaf curl New Delhi virus (ToLCNDV) with recently identified begomoviral isolates from two medicinal false daisy (Eclipta prostrata) and tomato (Solanum lycopersicum) plants. The ToLCNDV has become a significant limitation to vegetables production in many countries. A polymerase chain reaction was conducted to conserve the existence of begomoviral infection. The acquired amplicon was amplified using primers appropriate to the sequence in order to retrieve the full genome. The sequence analysis has confirmed the presence of ToLCNDV in symptomatic plants. The complete genome sequence having a 2.6–2.7 kb entire genome of ToLCNDV was obtained. An investigation of the phylogenetic and evolutionary history has verified the connection between this virus and other closely related viruses. The available nucleotide frequencies of codon regions (A, T/U, C, G) with newly isolates revealed 20–28% substitution matrixes. There was a minimal difference of nucleotide frequencies’ with already submitted database of this virus. Substitution matrixes, which quantify the probability of nucleotide substitutions evolving over a period of time, offer valuable information about mutation patterns and the forces driving evolution. This comparative analysis enhanced the comprehension of the genetic diversity of ToLCNDV and its possible consequences on medicinal plants. It also assisted in the formulation of efficient control measures and the preservation of begomoviruses in medicinal plant biodiversity. The information presented here is highly valuable for understanding the ToLCNDV biology and epidemiology, and it would also assist in disease management in the future.

Addressing epistasis in the design of protein function

Mutations in protein active sites can dramatically improve function. The active site, however, is densely packed and extremely sensitive to mutations. Therefore, some mutations may only be tolerated in combination with others in a phenomenon known as epistasis. Epistasis reduces the likelihood of obtaining improved functional variants and dramatically slows natural and lab evolutionary processes. Research has shed light on the molecular origins of epistasis and its role in shaping evolutionary trajectories and outcomes. In addition, sequence- and AI-based strategies that infer epistatic relationships from mutational patterns in natural or experimental evolution data have been used to design functional protein variants. In recent years, combinations of such approaches and atomistic design calculations have successfully predicted highly functional combinatorial mutations in active sites. These were used to design thousands of functional active-site variants, demonstrating that, while our understanding of epistasis remains incomplete, some of the determinants that are critical for accurate design are now sufficiently understood. We conclude that the space of active-site variants that has been explored by evolution may be expanded dramatically to enhance natural activities or discover new ones. Furthermore, design opens the way to systematically exploring sequence and structure space and mutational impacts on function, deepening our understanding and control over protein activity.

Whole Exome Sequencing of Intermediate-Risk Acute Myeloid Leukemia without Recurrent Genetic Abnormalities Offers Deeper Insights into New Diagnostic Classifications.

Two new diagnostic classifications of acute myeloid leukemia (AML) were published in 2022 to update current knowledge on disease biology. In previous 2017-edition categories of AML with myelodysplasia-related changes, AML was not otherwise specified, but AML with mutated RUNX1 experienced profound changes. We performed whole exome sequencing on a cohort of 69 patients with cytogenetic intermediate-risk AML that belonged to these diagnostic categories to correlate their mutational pattern and copy-number alterations with their new diagnostic distribution. Our results show that 45% of patients changed their diagnostic category, being AML myelodysplasia-related the most enlarged, mainly due to a high frequency of myelodysplasia-related mutations (58% of patients). These showed a good correlation with multilineage dysplasia and/or myelodysplastic syndrome history, but at the same time, 21% of de novo patients without dysplasia also presented them. RUNX1 was the most frequently mutated gene, with a high co-occurrence rate with other myelodysplasia-related mutations. We found a high prevalence of copy-neutral loss of heterozygosity, frequently inducing a homozygous state in particular mutated genes. Mild differences in current classifications explain the diagnostic disparity in 10% of patients, claiming a forthcoming unified classification.

Viral escape mutations do not account for non-protection from SIVmac239 challenge in RhCMV/SIV vaccinated rhesus macaques.

Simian immunodeficiency virus (SIV) vaccines based upon 68-1 Rhesus Cytomegalovirus (RhCMV) vectors show remarkable protection against pathogenic SIVmac239 challenge. Across multiple independent rhesus macaque (RM) challenge studies, nearly 60% of vaccinated RM show early, complete arrest of SIVmac239 replication after effective challenge, whereas the remainder show progressive infection similar to controls. Here, we performed viral sequencing to determine whether the failure to control viral replication in non-protected RMs is associated with the acquisition of viral escape mutations. While low level viral mutations accumulated in all animals by 28 days-post-challenge, which is after the establishment of viral control in protected animals, the dominant circulating virus in virtually all unprotected RMs was nearly identical to the challenge stock, and there was no difference in mutation patterns between this cohort and unvaccinated controls. These data definitively demonstrate that viral mutation does not explain lack of viral control in RMs not protected by RhCMV/SIV vaccination. We further demonstrate that during chronic infection RhCMV/SIV vaccinated RMs do not acquire escape mutation in epitopes targeted by RhCMV/SIV, but instead display mutation in canonical MHC-Ia epitopes similar to unvaccinated RMs. This suggests that after the initial failure of viral control, unconventional T cell responses induced by 68-1 RhCMV/SIV vaccination do not exert strong selective pressure on systemically replicating SIV.

Genomic mutation patterns and prognostic value in de novo and secondary acute myeloid leukemia: A multicenter study from China.

Acute myeloid leukemia (AML) can manifest as de novo AML (dn-AML) or secondary AML (s-AML), with s-AML being associated with inferior survival and distinct genomic characteristics. The underlying reasons for this disparity remain to be elucidated. In this multicenter study, next-generation sequencing (NGS) was employed to investigate the mutational landscape of AML in 721 patients from June 2020 to May 2023.Genetic mutations were observed in 93.34% of the individuals, with complex variations (more than three gene mutations) present in 63.10% of them. TET2, ASXL1, DNMT3A, TP53 and SRSF2 mutations showed a higher prevalence among older individuals, whereas WT1 and KIT mutations were more commonly observed in younger patients. BCOR, BCORL1, ZRSR2, ASXL1 and SRSF2 exhibited higher mutation frequencies in males. Additionally, ASXL1, NRAS, PPMID, SRSF2, TP53 and U2AF1 mutations were more common in patients with s-AML, which PPM1D was more frequently associated with therapy-related AML (t-AML). Advanced age and hyperleukocytosis independently served as adverse prognostic factors for both types of AML; however, s-AML patients demonstrated a greater number of monogenic adverse prognostic factors compared to dn-AML cases (ASXL1, PPM1D, TP53 and U2AF1 in s-AML vs. FLT3, TP53 and U2AF1 in dn-AML). Age and sex-related gene mutations suggest epigenetic changes may be key in AML pathogenesis. The worse prognosis of s-AML compared to dn-AML could be due to the older age of s-AML patients and more poor-prognosis gene mutations. These findings could improve AML diagnosis and treatment by identifying potential therapeutic targets and risk stratification biomarkers.

Phenotype-genotype spectrum of a cohort of congenital muscular dystrophies: a single-centre experience from India.

Congenital Muscular Dystrophies (CMD) are phenotypically and genotypically heterogenous disorders with a prevalence of 0.68 to 2.5/100,000, contributing to significant morbidity and mortality. We aimed to study the phenotype-genotype spectrum of genetically confirmed cases of CMD. This was retrospective & descriptive study done at a quaternary care referral centre in south India. Genetically confirmed cases of CMDs seen between 2010 to 2020 were recruited. Detailed clinical history, including pedigree, MRI brain/muscle, next generation sequencing results of 61 CMD cases were collected. Collagen VI-related dystrophy (COL6-RD) (36%) was the most common subtype with variants frequently seen in COL6A1 gene. Other CMDs identified were LAMA2-RD (26%), alpha-dystroglycan-RD (19%), LMNA-RD (8%), CHKB-RD (7%) and SEPN1-RD (3%). Similar to previous cohorts, overall, missense variants were common in COL-6 RD. Variants in triple helical domain (THD) of COL6-RD were seen in 11/22 patients, 5 of whom were ambulatory contrary to previous literature citing severe disease with these variants. However, our follow-up period was shorter. In the LAMA2-RD, 2/16 patients were ambulatory & all 16 carried truncating variants. Among dystroglycanopathies, FKRP-RD was the commonest. Milder phenotype of FKRP- RD was observed with variant c.1343C > T, which was also a recurrent variant in our cohort. p.Arg249Trp variant in LMNA-CMD associated with early loss of ambulation was also identified in 1/5 of our patients who expired at age 2.8years. The current retrospective series provides detailed clinical features and mutation patterns of genetically confirmed cases of CMD from a single center in India.

Analysis of the recombination and evolution of the new type mutant pseudorabies virus XJ5 in China

Pseudorabies have caused enormous economic losses in China’s pig industry and have recurred on many large pig farms since late 2011. The disease is caused by highly pathogenic, antigenic variant pseudorabies virus (vPRV) strains. Our laboratory isolated a pseudorabies virus in 2015 and named it XJ5. The pathogenic ability of this mutant strain was much stronger than that of the original isolate. After we sequenced its whole genome (GenBank accession number: OP512542), we found that its overall structure was not greatly changed compared with that of the previous strain Ea (KX423960.1). The whole genome alignment showed that XJ5 had a strong genetic relationship with the strains isolated in China after 2012 reported in GenBank. Based on the isolation time of XJ5 and the mutation and recombination analysis of programs, we found that the whole genome homology of XJ5 and other strains with Chinese isolates was greater than 95%, while the homology with strains outside Asia was less than 94%, which indicated that there may be some recombination and mutation patterns. We found that virulent PRV isolates emerged successively in China in 2011 and formed two different evolutionary clades from foreign isolates. At the same time, this may be due to improper immunization and the presence of wild strains in the field, and recent reports have confirmed that Bartha vaccine strains recombine with wild strains to obtain new pathogenic strains. We performed genetic evolution analysis of XJ5 isolated and sequenced in our laboratory to trace its possible mutations and recombination. We found that XJ5 may be the result of natural mutation of a virus in a branch of mutant strains widely existing in China.

Colibactin leads to a bacteria-specific mutation pattern and self-inflicted DNA damage.

Colibactin produced primarily by Escherichia coli strains of the B2 phylogroup cross-links DNA and can promote colon cancer in human hosts. Here, we investigate the toxin's impact on colibactin producers and on bacteria cocultured with producing cells. Using genome-wide genetic screens and mutation accumulation experiments, we uncover the cellular pathways that mitigate colibactin damage and reveal the specific mutations it induces. We discover that although colibactin targets A/T-rich motifs, as observed in human colon cells, it induces a bacteria-unique mutation pattern. Based on this pattern, we predict that long-term colibactin exposure will culminate in a genomic bias in trinucleotide composition. We test this prediction by analyzing thousands of E. coli genomes and find that colibactin-producing strains indeed show the predicted skewness in trinucleotide composition. Our work reveals a bacteria-specific mutation pattern and suggests that the resistance protein encoded on the colibactin pathogenicity island is insufficient in preventing self-inflicted DNA damage.

Pax7 is involved in leucophore formation in goldfish and gene knockout improves the transparency of transparent goldfish.

Lines with few or no pigment cells have been established in fishes, and these lines are useful for bioimaging. The transparent goldfish (tra) line previously established by N-ethyl-N-nitrosourea (ENU) mutagenesis is also suitable for such experiments. However, in the case of tra, leucophores form in the adult fish, making it difficult to observe the organs inside body from outside the body. In this study, we attempted to create a knockout line of the pax7a and pax7b genes, which are thought to be involved in the formation of leucophores, to further improve the transparency of tra strain.Mutations were introduced by microinjection of the CRISPR/Cas9 mixture into single-cell embryos, mutant individuals were found in F0, and the next generation was generated to confirm the mutation patterns. As a result, multiple mutation patterns, including knockout, were obtained. The same pattern of knockout F1 with pax7a and pax7b mutations was crossed to generate a homozygous knockout in F2.In the resulting pax7b-/- (tra) fish but not in pax7a-/- (tra) fish, the number of leucophores was reduced compared to that in tra, and the transparency of the body was improved. It was suggested that pax7b plays an important role in leucophore formation in goldfish. The established transparent pax7b-/- (tra) goldfish line will be a useful model for bioimaging of the body interior.

ERCC2 mutations alter the genomic distribution pattern of somatic mutations and are independently prognostic in bladder cancer

Excision repair cross-complementation group 2 (ERCC2) encodes the DNA helicase xeroderma pigmentosum group D, which functions in transcription and nucleotide excision repair. Point mutations in ERCC2 are putative drivers in around 10% of bladder cancers (BLCAs) and a potential positive biomarker for cisplatin therapy response. Nevertheless, the prognostic significance directly attributed to ERCC2 mutations and its pathogenic role in genome instability remain poorly understood. We first demonstrated that mutant ERCC2 is an independent predictor of prognosis in BLCA. We then examined its impact on the somatic mutational landscape using a cohort of ERCC2 wild-type (n= 343) and mutant (n= 39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in ERCC2 mutants, including T[C>T]N enrichment, altered replication time correlations, and CTCF-cohesin binding site mutation hotspots. We leverage these alterations to develop a machine learning model for predicting pathogenic ERCC2 mutations, which may be useful to inform treatment of patients with BLCA.

Genomic patterns of somatic mutations provide new prognostic, therapeutic, and biological insights in cancer

The mutational landscape of an individual's cancer can inform on its molecular state and be used as prognostic and therapeutic markers. The study by Barbour etal.1 analyzes mutational patterns in bladder cancer samples to uncover new biological insights into the ERCC2 gene function and develop new predictive prognostic tools.

RNF43 in cancer: Molecular understanding and clinical significance in immunotherapy.

Identifying biomarkers to predict immune checkpoint inhibitor (ICI) efficacy is warranted. Considering that somatic mutation-derived neoantigens induce strong immune responses, patients with a high tumor mutational burden reportedly tend to respond to ICIs. Therefore, the original function of neoantigenic mutations and their impact on the tumor microenvironment (TME) require attention. RNF43 is a type of RING E3 ubiquitin ligase, and long-term survivors in most cancers had conserved patterns of mutations of RNF43. Also, high microsatellite instability patients had a higher RNF43 mutation rate compared with microsatellite stability tumor patients, who were more sensitive to ICI treatment. Therefore, RNF43 has become a promising biomarker of immunotherapy in a wide range of cancers. This review focuses on the up-to-date knowledge of RNF43 mutation in cancer. We summarize the cancer hallmarks involving activities regulated by RNF43 and highlight its extremely sophisticated regulation of WNT signaling and tumor microenvironment. The key genes interacting with RNF43 have also been summarized and discussed. Additionally, we highlight and propose new strategies of targeting RNF43 and RNF43-based combinations with established immunotherapy and combination therapy. These efforts may provide new perspectives for RNF43-based target therapy in cancer.

A Six-gene Prognostic Model Based on Neutrophil Extracellular Traps (NETs)-related Gene Signature for Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the most common malignant cancers. Neutrophil extracellular traps (NETs) have been discovered to play a crucial role in the pathogenesis of LUAD. We aimed to establish an innovative prognostic model for LUAD based on the distinct expression patterns of NETs-related genes. The TCGA LUAD dataset was utilized as the training set, while GSE31210, GSE37745, and GSE50081 were undertaken as the verification sets. The patients were grouped into clusters based on the expression signature of NETs-related genes. Differentially expressed genes between clusters were identified through the utilization of the random forest and LASSO algorithms. The NETs score model for LUAD prognosis was developed by multiplying the expression levels of specific genes with their corresponding LASSO coefficients and then summing them. The validity of the model was confirmed by analysis of the survival curves and ROC curves. Additionally, immune infiltration, GSEA, mutation analysis, and drug analysis were conducted. Silencing ABCC2 in A549 cells was achieved to investigate its effect. We identified six novel NETs-related genes, namely UPK1B, SFTA3, GGTLC1, SCGB3A1, ABCC2, and NTS, and developed a NETs score signature, which exhibited a significant correlation with the clinicopathological and immune traits of the LUAD patients. High-risk patients showed inhibition of immune-related processes. Mutation patterns exhibited variability among the different groups. AZD3759, lapatinib, and dasatinib have been identified as potential candidates for LUAD treatment. Moreover, the downregulation of ABCC2 resulted in the induction of apoptosis and suppression of migration and invasion in A549 cells. Altogether, this study has identified a novel NET-score signature based on six novel NET-related genes to predict the prognosis of LUAD and ABCC2 and has also explored a new method for personalized chemo-/immuno-therapy of LUAD.

Integrated Single-cell and Bulk RNA Sequencing Analysis Cross Talk between Ferroptosis-related Genes and Prognosis in Oral Cavity Squamous Cell Carcinoma.

Ferroptosis is a new type of programmed apoptosis and plays an important role in tumour inhibition and immunotherapy. In this study, we aimed to explore the potential role of ferroptosis-related genes (FRGs) and the potential therapeutic targets in oral cavity squamous cell carcinoma (OCSCC). The transcription data of OCSCC samples were obtained from the Cancer Genome Atlas (TCGA) database as a training dataset. The prognostic FRGs were extracted by univariate Cox regression analysis. Then, we constructed a prognostic model using the least absolute shrinkage and selection operator (LASSO) and Cox analysis to determine the independent prognosis FRGs. Based on this model, risk scores were calculated for the OCSCC samples. The model's capability was further evaluated by the receiver operating characteristic curve (ROC). Then, we used the GSE41613 dataset as an external validation cohort to confirm the model's predictive capability. Next, the immune infiltration and somatic mutation analysis were applied. Lastly, single-cell transcriptomic analysis was used to identify the key cells. A total of 12 prognostic FRGs were identified. Eventually, 6 FRGs were screened as independent predictors and a prognostic model was constructed in the training dataset, which significantly stratified OCSCC samples into high-risk and low-risk groups based on overall survival. The external validation of the model using the GSE41613 dataset demonstrated a satisfactory predictive capability for the prognosis of OCSCC. Further analysis revealed that patients in the highrisk group had distinct immune infiltration and somatic mutation patterns from low-risk patients. Mast cell infiltrations were identified as prognostic immune cells and played a role in OCSCC partly through ferroptosis. We successfully constructed a novel 6 FRGs model and identified a prognostic immune cell, which can serve to predict clinical prognoses for OCSCC. Ferroptosis may be a new direction for immunotherapy of OCSCC.

Whole-Exome Sequencing of Vulvar Squamous Cell Carcinomas Reveals an Impaired Prognosis in Patients With TP53 Mutations and Concurrent CCND1 Gains

Very little information is available on the mutational landscape of vulvar squamous cell carcinoma (VSCC), a disease that mainly affects older women. Studies focusing on the mutational patterns of the currently recognized etiopathogenic types of this tumor (human papillomavirus [HPV]-associated [HPV-A], HPV-independent [HPV-I] with TP53 mutation [HPV-I/TP53mut], and HPV-I with wild-type TP53 [HPV-I/TP53wt]) are particularly rare, and there is almost no information on the prognostic implications of these abnormalities.Whole-exome DNA sequencing of 60 VSCC and matched normal tissues from each patient was performed. HPV detection, immunohistochemistry (IHC) for p16, p53, and mismatch repair proteins were also performed. Ten tumors (16.7%) were classified as HPV-A, 37 (61.7%) as HPV-I/TP53mut, and 13 (21.6%) as HPV-I/TP53wt. TP53 was the most frequently mutated gene (66.7%), followed by FAT1 (28.3%), CDKN2A (25.0%), RNF213 (23.3%), NFE2L2 (20%) and PIK3CA (20%). All the 60 tumors (100%) were DNA mismatch repair proficient. Seventeen tumors (28.3%) showed CCND1 gain. Bivariate analysis, adjusted for International Federation of Gynecology and Obstetrics stage, revealed that TP53 mutation, CCND1 gain, and the combination of the 2 alterations were strongly associated with impaired recurrence-free survival (hazard ratio, 4.4; P < .001) and disease-specific survival (hazard ratio, 6.1; P = .002). Similar results were obtained when p53 IHC status was used instead of TP53 status and when considering only HPV-I VSCC. However, in the latter category, p53 IHC maintained its prognostic impact only in combination with CCND1 gains. All tumors carried at least one potentially actionable genomic alteration. In conclusion, VSCCs with CCND1 gain represent a prognostically adverse category among HPV-I/TP53mut tumors. All patients with VSCCs are potential candidates for targeted therapy.

Single nucleotide and copy number variants of cancer driver genes inform drug response in multiple cancers.

Due to the heterogeneity of cancer, precision medicine has been a major challenge for cancer treatment. Determining medication regimens based on patient genotypes has become a research hotspot in cancer genomics. In this study, we aim to identify key biomarkers for targeted therapies based on single nucleotide variants (SNVs) and copy number variants (CNVs) of genes. The experiment is carried out on 7 cancers on the Encyclopedia of Cancer Cell Lines (CCLE) dataset. Considering the high mutability of driver genes which result in abundant mutated samples, the effect of data sparsity can be eliminated to a large extent. Therefore, we focus on discovering the relationship between driver mutation patterns and three measures of drug response, namely area under the curve (AUC), half maximal effective concentration (EC50), and log2-fold change (LFC). First, multiple statistical methods are applied to assess the significance of difference in drug response between sample groups. Next, for each driver gene, we analyze the extent to which its mutations can affect drug response. Based on the results of multiple hypothesis tests and correlation analyses, our main findings include the validation of several known drug response biomarkers such as BRAF, NRAS, MAP2K1, MAP2K2, and CDKN2A, as well as genes with huge potential to infer drug responses. It is worth emphasizing that we identify a list of genes including SALL4, B2M, BAP1, CCDC6, ERBB4, FOXA1, GRIN2A, and PTPRT, whose impact on drug response spans multiple cancers and should be prioritized as key biomarkers for targeted therapies. Furthermore, based on the statistical p-values and correlation coefficients, we construct gene-drug sensitivity maps for cancer drug recommendation. In this work, we show that driver mutation patterns could be used to tailor therapeutics for precision medicine.

Morphological and immunohistochemical evaluation in distinguishing post-radiotherapy serous-like endometrial change (PoRSEC) and serous endometrial intraepithelial carcinoma (SEIC).

Uteri from women undergoing chemoradiotherapy (CRT) may show reactive atypia which may mimic serous endometrial intraepithelial carcinoma (SEIC). We aimed to assess the prevalence and morphological/immunohistochemical features of post-radiotherapy serous-like endometrial changes (PoRSEC) in women undergone CRT for locally advanced cervical cancer, with a focus on the differential diagnosis with SEIC. Consecutive patients with locally advanced cervical cancer undergone CRT between 2011 and 2018 were reviewed. Endometrial histological specimens were assessed for the presence of PoRSEC. Twenty-two cases of SEIC were included for comparison. Immunohistochemistry for p53, p16, and Ki67 was performed. Out of 244 reviewed patients, 36 (14.7%) showed PoRSEC. The degree of nuclear atypia was similar between PoRSECs and SEIC. However, a papillary architecture with areas of confluent papillae was only observed in SEIC. SEIC cases showed a high mitotic activity as opposed to PoRSEC cases. The expression of p53 was aberrant in all SEICs but in none of the PoRSECs; however, 13/36 PoRSECs showed p53 positivity in most tumor cells, potentially mimicking a mutation pattern. A block-type p16 expression was observed in all SEICs and in 16/36 PoRSECs. Mean Ki67 expression was 26.9% in SEIC (range 5-70%) and 8.16% in PoRSEC (range 5-35%). While SEIC showed sharp morphological and immunohistochemical demarcation, PoRSEC were more heterogenous and merged imperceptibly with normal endometrium. In conclusion, PoRSEC may mimic SEIC both morphologically and immunohistochemically. However, a papillary architecture with cytological demarcation is typically observed in SEIC but not in PoRSEC.